1. Field of the Invention
The present invention is directed toward new isoxazolinones, methods for their use, and processes for their production. The present invention provides for a compound represented by the general formula 
or a pharmaceutically acceptable salt thereof wherein:
R1 is
a) H,
b) C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy, or C1-8 acyloxy,
c) C3-6 cycloalkyl, or
d) C1-8 alkoxy;
L is oxygen or sulfur;
A is 
c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R8,
d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R9,
e) a xcex2-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R9, 
wherein R2 and R3 are each independently
a) H,
b) F,
c) Cl,
d) Br,
e) C1-6 alkyl,
f) NO2,
g) I,
h) C1-6 alkoxy,
i) OH
j) amino,
k) cyano, or
l) R2 and R3 taken together are xe2x80x94O(CH2)hxe2x80x94O;
wherein R4 is
a) H,
b) C1-2 alkyl,
c) F, or
d) OH;
R5 is
a) H,
b) CF3,
c) C1-3 alkyl optionally substituted with one or more halo,
d) phenyl optionally substituted with one or more halo,
e) R5 and R6 taken together are a 5-, 6-, or 7-membered ring of the formula, 
xe2x80x83in which D is S, O or NR86 in which R86 is H or C1-6 alkyl or
g) R5 and R6 taken together are xe2x80x94(CH2)kxe2x80x94, when R7 is an electron-withdrawing group;
R6 and R7 at each occurrence are the same or different and are
a) an electron-withdrawing group,
b) H,
c) CF3,
d) C1-3 alkyl optionally substituted with one halo,
e) phenyl, provided at least one of R6 and R7 is an electron-withdrawing group, or
f) R6 and R7 taken together are a 5-, 6-, or 7-membered ring of the formula, 
U is
a) CH2,
b) O,
c) S or,
d) NR16;
R16 is
a) H or
b) C1-5 alkyl;
wherein R8 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) xe2x80x94NR17R18, 
xe2x80x83in which R87 is H or C1-6 alkyl,
n) C1-6 alkyl optionally substituted with OH, sulfamoyl, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR17R18,
o) C2-8 alkyl optionally substituted with one or two R19,
p) phenyl optionally substituted with one or two R19,
q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R19, or 
R17 and R18 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl,
c) C5-6 cycloalkyl, or
d) R17 and R18 taken together with the nitrogen atom is a 5- or 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1-3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety containing 1-3 O, N or S, 
xe2x80x83in which R88 and R89 are each independently hydrogen or C1-6 alkyl, SO2R90 in which R90 is H or C1-6 alkyl, or C1-3 acyl optionally substituted with 1 or more F, Cl or OH;
R19 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
i) C1-6 alkythio,
k) C1-6 acyl,
l) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR17R18,
m) phenyl,
n) xe2x80x94C(xe2x95x90O)NR20R21,
o) xe2x80x94N R17R18,
p) xe2x80x94N(R20)(xe2x80x94SO2R22),
q) xe2x80x94SO2xe2x80x94NR20R21, or
r) xe2x80x94S(xe2x95x90O)iR22;
R20 and R21 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl, or
c) phenyl;
R22 is
a) C1-4 alkyl, or
b) phenyl optionally substituted with C1-4 alkyl;
wherein R9 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) xe2x80x94NR23R24,
m) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR23R24,
n) C2-8 alkenylphenyl optionally substituted with one or two R25,
o) phenyl optionally substituted with one or two R25,
p) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or 
R23 and R24 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl, or
g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl;
R25 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) phenyl,
m) C1-6 alkyl optionally substituted with OH, azido, C1-5 alkoxy, C1-5 acyl, xe2x80x94NR32R33, xe2x80x94SR34, xe2x80x94Oxe2x80x94SO2R35, or 
n) xe2x80x94C(xe2x95x90O)NR26R27,
o) xe2x80x94NR23R24,
p) xe2x80x94N(R26)(xe2x80x94SO2R22),
q) xe2x80x94SO2xe2x80x94NR26R27, or
r) xe2x80x94S(xe2x95x90O)iR22,
s) xe2x80x94CHxe2x95x90Nxe2x80x94R28, or
t) xe2x80x94CH(OH)xe2x80x94SO3R31;
R22 is the same as defined above;
R26 and R27 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl,
c) phenyl, or
d) tolyl;
R28 is
a) OH,
b) benzyloxy,
c) xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2,
d) xe2x80x94NHxe2x80x94C(xe2x95x90S)xe2x80x94NH2, or
e) xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NR29R30;
R29 and R30 at each occurrence are the same or different and are
a) H,or
b) C1-4 alkyl optionally substituted with phenyl or pyridyl;
R31 is
a) H, or
b) a sodium ion;
R32 and R33 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl,
g) R32 and R33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl,
h) xe2x80x94P(O)(OR37)(OR38), or
i) xe2x80x94SO2xe2x80x94R39;
R34 is 
R35 is C1-3 alkyl;
R36 is
a) C1-6 alkoxycarbonyl, or
b) carboxyl;
R37 and R38 at each occurrence are the same or different and are
a) H,or
b) C1-3 alkyl;
R39 is
a) methyl,
b) phenyl, or
c) tolyl;
wherein K is
a) O,
b) S, or
c) NR40 in which R40 is hydrogen, formyl, C1-4 alkyl, C1-4 acyl, phenyl, C3-6 cycloalkyl, xe2x80x94P(O)(OR37)(OR38) or xe2x80x94SO2xe2x80x94R39 in which R37, R38 and R39 are as defined above;
R10, R11, R12, R13, R14 and R15 at each occurrence are the same or different and are
a) H,
b) formyl,
c) carboxyl,
d) C1-6 alkoxycarbonyl,
e) C1-8 alkyl,
f) C2-8 alkenyl,
wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C1-6 alkoxyl, C1-6 acyl, C1-6 alkylthio or C1-6 alkoxycarbonyl, or phenyl optionally substituted with halo,
g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
h) xe2x80x94NR42R43,
i) OR44,
j) xe2x80x94S(xe2x95x90O)ixe2x80x94R45,
k) xe2x80x94SO2xe2x80x94N(R46)(R47), or
l) a radical of the following formulas: 
R19 is the same as defined above;
T is
a) O,
b) S, or
c) SO2;
R42 and R43 at each occurrence are the same or different and are
a) H,
b) C3-6 cycloalkyl,
c) phenyl,
d) C1-6 acyl,
e) C1-8 alkyl optionally substituted with OH, C1-6 alkoxy which can be substituted with OH, a 5- or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, xe2x80x94NO2, C1-4 , alkoxy, xe2x80x94NR48R49, or 
V is
a) O,
b) CH2, or
c) NR56;
R48 and R49 at each occurrence are the same or different and are
a) H, or
b) C1-4 alkyl;
R54 is
a) OH,
b) C1-4 alkoxy, or
c) xe2x80x94NR57R58;
R55 is
a) H, or
b) C1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, xe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94CO2H, or xe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R56 is
a) H,
b) phenyl, or
c) C1-6 alkyl optionally substituted by OH;
R57 and R58 at each occurrence are the same or different and are
a) H,
b) C1-5 alkyl,
c) C1-3 cycloalkyl, or
d) phenyl;
R44 is
a) C1-8 alkyl optionally substituted with C1-6 alkoxy or C1-6 hydroxy, C3-6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl, 
c) phenyl, or
d) pyridyl;
R45 is
a) C1-16 alkyl,
b) C2-16 alkenyl,
wherein the substituents (a) and (b) can be optionally substituted with C1-6 alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O,
c) an aromatic moiety having 6 to 10 carbon atoms, or
d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, xe2x80x94NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
R46 and R47 at each occurrence are the same or different and are
a) H,
b) phenyl,
c) C1-6 alkyl, or
d) benzyl;
R50 and R51 at each occurrence are the same or different and are
a) H,
b) OH,
c) C1-6 alkyl optionally substituted with xe2x80x94NR48R49 in which R48 and R49 are as defined above,
d) R50 and R51 taken together are xe2x95x90O;
R52 is
a) an aromatic moiety having 6 to 10 carbon atoms,
b) a 5- or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) can in turn be optionally substituted with one or three xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, phenyl, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl,
c) morpholinyl,
d) OH,
e) C1-6 alkoxy,
f) xe2x80x94NR48R49 in which R48 and R49 are as defined above,
g) xe2x80x94C(xe2x95x90O)xe2x80x94R59, or 
R53 is
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl,
g) xe2x80x94P(O)(OR37)(OR38), or
h) xe2x80x94SO2R39, in which R37, R38 and R39 are as defined above;
R59 is
a) morpholinyl,
b) OH, or
c) C1-6 alkoxy;
h is 1, 2, or 3;
i is 0, 1, or 2;
j is 0, or 1;
k is 3, 4, or 5;
r is 1, 2, 3, 4, 5 or 6;
t is 0, 1, 2, 3, 4, 5, or 6;
u is 1 or 2; and
Q is
a) hydrogen,
b) halo,
c) NO2,
d) N3,
e) C1-C6 alkylthio, 
h) C1-C6 alkyl,
i) C1-C6 alkoxy,
j) formyl, 
m) xe2x80x94sulfamoyl (H2NSO2xe2x80x94),
n) xe2x80x94NHOH, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 
r) amino,
s) C1-C6 alkylamino-,
t) di (C1-C6 alkyl)amino-, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
V) OH,
w) cyano,
x) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
xe2x80x83in which R84 is hydrogen or C1-6 alkyl, 
xe2x80x83in which R85 is hydrogen, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy; 
xe2x80x83in which R84 is hydrogen or C1-6 alkyl,
ff) a substituted or unsubstituted C6-C10 aryl moiety,
gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent,
hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring;
the substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following:
1) halo,
2) C1-6 alkyl,
3) NO2,
4) N3, 
7) formyl, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
13) OH,
14) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
18) xe2x80x94CH2xe2x80x94R80 in which R80 is
a) xe2x80x94OR32 in which R32 is as defined above,
b) xe2x80x94SR32 in which R32 is as defined above,
c) xe2x80x94NR32R33 in which R32 and R33 are as defined above, or
d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, 
xe2x80x83in which R84 is as defined above,
20) cyano,
21) carboxyl,
22) CF3, 
xe2x80x83in which the phenyl moiety may be optionally substituted by halo or (C1-C6)alkyl, 
xe2x80x83in which R60 and R61 are as defined above, 
xe2x80x83in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S, 
xe2x80x83in which R85 is as defined above, 
xe2x80x83in which R99, R100 and R101 are each independently C1-6 alkyl; or
Q and either R1 and R2 taken together form xe2x80x94Oxe2x80x94CH2xe2x80x94O.
These derivatives are useful as antimicrobial agents which are effective against a number of human and veterinary pathogens, including gram positive bacteria such as multiply-resistant staphylococci, streptococci, and enterococci, such as methicillin-resistant Staphylococcus aureus or vancomycin-resistant Enterococcus faecium. 
2. Description of the Prior Art
The literature contains a limited number of isoxazolinones used as pre-emergence herbicides. For example in U.S. Pat. No. 4,065,463, 2-methyl4-(trifluoromethyl-m-tolyl)-3-isoxazolin-5-one and 2-methyl-4-(chloro-m-tolyl)-3-isoxazolin-5-one are disclosed as being useful in preventing the growth of weeds which have a deleterious effect on crop production. 
U.S. Pat. No. 4,000,155 discloses the related compound 1,2-dimethyl-4-(trifluoromethyl-m-tolyl)-3-pyrazolin-5-one for the same utility. 
The applicant is not aware of any literature which discloses the use of these compounds as broad spectrum anti-bacterial agents. A different ring system is disclosed in WO 98/07708, which discusses the use of isoxazoline derivatives as anti-bacterial agents, 
where W is a substituted aryl or heteroaryl system and V is H, or C1-C4 alkyl optionally substituted with F, Cl, OH, C1-C4 alkoxy, or acyloxy.
Oxazolidinones II shown below are a well known class of orally active antibacterial agents. The prior art contains numerous references to these compounds where Y and Z can include a wide variety of substituents. Specific substituted oxazolidinones are discussed in U.S. Pat. Nos. 4,705,799 and 5,523,403 (substituted phenyl 2-oxazolidinones), U.S. Pat. Nos. 4,948,801; 5,254,577; and 5,130,316 (arylbenzene oxazolidinyl compounds), and European Patent Applications 0,697,412; 0,694,544; 0694,543; and 0,693,491 (5 to 9-membered heteroaryl substituted oxazolidinones). 
Additionally, certain compounds containing a substituted furanone ring have been reported to possess antibiotic activity. WO 97/14690 discloses 
where T is hydroxy or NHC(O)C1-C4 alkyl, M and L are each independently hydrogen or fluoro, G and H are are each independently hydrogen or methyl, Kxe2x80x94J is of the formula Cxe2x95x90CH, CHCH2 or C(OH)CH2, I is O, SO, SO2 or a substituted nitrogen, and Qxe2x80x94R is CH2xe2x80x94CH2 or CHxe2x95x90CH2. Other substituted furanones are discussed in U.S. Pat. No. 5,708,169, WO 97/43280 and WO 97/10235.
It has now been found that certain substituted isoxazolinones are effective as antibacterial agents. Specifically, the invention covers compounds of the formula I: 
or a pharmaceutically acceptable salt thereof wherein:
R1 is
a) H,
b) C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy, or C1-8 acyloxy,
c) C3-6 cycloalkyl, or
d) C1-8 alkoxy;
L is oxygen or sulfur;
A is 
c) a 5-membered heteroaromatic moiety having one to three hetero atoms selected from the group consisting of S, N, and O, wherein the 5-membered heteroaromatic moiety is bonded via a carbon atom and can additionally have a fused-on benzene or naphthyl ring, and wherein the heteroaromatic moiety is optionally substituted with one to three R8,
d) a 6-membered heteroaromatic moiety having at least one nitrogen atom, wherein the heteroaromatic moiety is bonded via a carbon atom, wherein the 6-membered heteroaromatic moiety can additionally have a fused-on benzene or naphthyl ring, wherein the heteroaromatic moiety is optionally substituted with one to three R9,
e) a xcex2-carbolin-3-yl, or indolizinyl bonded via the 6-membered ring, optionally substituted with one to three R9, 
wherein R2 and R3 are each independently
a) H,
b) F,
c) Cl,
d) Br,
e) C1-6 alkyl,
f) NO2,
g) I,
h) C1-6 alkoxy,
i) OH
j) amino,
k) cyano, or
l) R2 and R3 taken together are xe2x80x94O(CH2)hxe2x80x94O;
wherein R4 is
a) H,
b) C1-2 alkyl,
c) F, or
d) OH;
R5 is
a) H,
b) CF3,
c) C1-3 alkyl optionally substituted with one or more halo,
d) phenyl optionally substituted with one or more halo,
e) R5 and R6 taken together are a 5-, 6-, or 7-membered ring of the formula, 
xe2x80x83in which D is S, O or NR86 in which R86 is H or C1-6 alkyl, or
g) R5 and R6 taken together are xe2x80x94(CH2)kxe2x80x94, when R7 is an electron-withdrawing group;
R6 and R7 at each occurrence are the same or different and are
a) an electron-withdrawing group,
b) H,
c) CF3,
d) C1-3 alkyl optionally substituted with one halo,
e) phenyl, provided at least one of R6 and R7 is an electron-withdrawing group, or
f) R6 and R7 taken together are a 5-, 6-, or 7-membered ring of the formula, 
U is
a) CH2,
b) O,
c) S or,
d) NR16;
R16 is
a) H or
b) C1-5 alkyl;
wherein R8 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) xe2x80x94NR17R18, 
xe2x80x83in which R87 is H or C1-6 alkyl,
n) C1-6 alkyl optionally substituted with OH, sulfamoyl, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR17R18,
o) C2-8 alkyl optionally substituted with one or two R19,
p) phenyl optionally substituted with one or two R19,
q) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R19, or 
R17 and R18 at each occurrence are the same or different and are
a) H,
b) C1-4 alkyl,
c) C5-6 cycloalkyl, or
d) R17 and R18 taken together with the nitrogen atom is a 5- or 6-membered saturated or unsaturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, C1-3 alkyl, formyl, a 5- or 6-membered heteroaromatic moiety containing 1-3 O, N or S, 
xe2x80x83in which R88 and R89 are each independently hydrogen or C1-6 alkyl, SO2R90 in which R90 is H or C1-6 alkyl, or C1-3 acyl optionally substituted with 1 or more F, Cl or OH;
R19 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
i) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR17R18,
m) phenyl,
n) xe2x80x94C(xe2x95x90O)NR20R21,
o) xe2x80x94N R17R18,
p) xe2x80x94N(R20)(xe2x80x94SO2R22),
q) xe2x80x94SO2xe2x80x94NR20R21, or
r) xe2x80x94S(xe2x95x90O)iR22;
R20 and R21 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl, or
c) phenyl;
R22 is
a) C1-4 alkyl, or
b) phenyl optionally substituted with C1-4 alkyl;
wherein R9 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
l) xe2x80x94NR23R24,
m) C1-6 alkyl optionally substituted with OH, C1-5 alkoxy, C1-5 acyl, or xe2x80x94NR23R24,
n) C2-8 alkenylphenyl optionally substituted with one or two R25,
o) phenyl optionally substituted with one or two R25,
p) a 5- or 6-membered saturated or unsaturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, optionally substituted with one or two R25, or 
R23 and R24 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl, or
g) R23 and R24 taken together with the nitrogen atom is a 5- or 6-membered saturated heterocyclic moiety which optionally has a further hetero atom selected from the group consisting of S, N, O, and can in turn be optionally substituted with, including on the further nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl;
R25 is
a) carboxyl,
b) halo,
c) xe2x80x94CN,
d) mercapto,
e) formyl,
f) CF3,
g) NO2,
h) C1-6 alkoxy,
i) C1-6 alkoxycarbonyl,
j) C1-6 alkythio,
k) C1-6 acyl,
i) phenyl,
m) C1-6 alkyl optionally substituted with OH, azido, C1-5 alkoxy, C1-5 acyl, xe2x80x94NR32R33, xe2x80x94SR34, xe2x80x94Oxe2x80x94SO2R35, or 
n) xe2x80x94C(xe2x95x90O)NR26R27,
o) xe2x80x94NR23R24,
p) xe2x80x94N(R26)(xe2x80x94SO2R22),
q) xe2x80x94SO2xe2x80x94NR26R27, or
r) xe2x80x94S(xe2x95x90O)iR22,
s) xe2x80x94CHxe2x95x90Nxe2x80x94R28, or
t) xe2x80x94CH(OH)xe2x80x94SO3R31;
R22 is the same as defined above;
R26 and R27 at each occurrence are the same or different and are
a) H,
b) C1-6 alkyl,
c) phenyl, or
d) tolyl;
R28 is
a) OH,
b) benzyloxy,
c) xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2,
d) xe2x80x94NHxe2x80x94C(xe2x95x90S)xe2x80x94NH2, or
e) xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NR29R30;
R29 and R30 at each occurrence are the same or different and are
a) H, or
b) C1-4 alkyl optionally substituted with phenyl or pyridyl;
R31 is
a) H, or
b) a sodium ion;
R32 and R33 at each occurrence are the same or different and are
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl,
g) R32 and R33 taken together are a 5- or 6-membered saturated heterocyclic moiety having one to three atoms selected from the group consisting of S, N, O, optionally substituted with, including on the nitrogen atom, phenyl, pyrimidyl, C1-3 alkyl, or C1-3 acyl,
h) xe2x80x94P(O)(OR37)(OR38), or
i) xe2x80x94SO2xe2x80x94R39;
R34 is 
R35 is C1-3 alkyl;
R36 is
a) C1-6 alkoxycarbonyl, or
b) carboxyl;
R37 and R38 at each occurrence are the same or different and are
a) H,or
b) C1-3 alkyl;
R39 is
a) methyl,
b) phenyl, or
c) tolyl;
wherein K is
a) O,
b) S, or
c) NR40 in which R40 is hydrogen, formyl, C1-4 alkyl, C1-4 acyl, phenyl, C3-6 cycloalkyl, xe2x80x94P(O)(OR37)(OR38) or xe2x80x94SO2xe2x80x94R39 in which R37, R38 and R39 are as defined above;
R10, R11, R12, R13, R14 and R15 at each occurrence are the same or different and are
a) H,
b) formyl,
c) carboxyl,
d) C1-6 alkoxycarbonyl,
e) C1-8 alkyl,
f) C2-8 alkenyl,
wherein the substitutents (e) and (f) can be optionally substituted with OH, halo, C1-6alkoxyl, C1-6acyl, C1-6alkylthio or C1-6, alkoxycarbonyl, or phenyl optionally substituted with halo,
g) an aromatic moiety having 6 to 10 carbon atoms optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
h) xe2x80x94NR42R43,
i) OR44,
xe2x80x94S(xe2x95x90O)ixe2x80x94R45,
k) xe2x80x94SO2xe2x80x94N(R46)(R47), or
l) a radical of the following formulas: 
R19 is the same as defined above;
T is
a) O,
b) S, or
c) SO2;
R42 and R43 at each occurrence are the same or different and are
a) H,
b) C3-6 cycloalkyl,
c) phenyl,
d) C1-6 acyl,
e) C1-8 alkyl optionally substituted with OH, C1-6 alkoxy which can be substituted with OH, a 5- or 6-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, phenyl optionally substituted with OH, CF3, halo, xe2x80x94NO2, C1-4 alkoxy,xe2x80x94NR48R49, or 
V is
a) O,
b) CH2, or
c) NR56;
R48 and R49 at each occurrence are the same or different and are
a) H, or
b) C1-4 alkyl;
R54 is
a) OH,
b) C1-4 alkoxy, or
c) xe2x80x94NR57R58;
R55 is
a) H, or
b) C1-7 alkyl optionally substituted with indolyl, OH, mercaptyl, imidazoly, methylthio, amino, phenyl optionally substituted with OH, xe2x80x94C(xe2x95x90O)xe2x80x94NH2, xe2x80x94CO2H, or xe2x80x94C(xe2x95x90NH)xe2x80x94NH2;
R56 is
a) H,
b) phenyl, or
c) C1-6 alkyl optionally substituted by OH;
R57 and R58 at each occurrence are the same or different and are
a) H,
b) C1-5 alkyl,
c) C1-3 cycloalkyl, or
d) phenyl;
R44 is
a) C1-8 alkyl optionally substituted with C1-6 alkoxy or C1-6 hydroxy, C3-6 cycloalkyl, a 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three nitrogen atoms, which can in turn be substituted with one or two xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl, 
c) phenyl, or
d) pyridyl;
R45 is
a) C1-16 alkyl,
b) C2-16 alkenyl,
wherein the substituents (a) and (b) can be optionally substituted with C1-6 alkoxycarbonyl, or a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O,
c) an aromatic moiety having 6 to 10 carbon atoms, or
d) a 5-, 6-, or 7-membered aromatic heterocyclic moiety having one to three atoms selected from the group of S, N, and O, wherein the substituents (c) and (d) can be optionally substituted with carboxyl, halo, xe2x80x94CN, formyl, CF3, xe2x80x94NO2, C1-6 alkyl, C1-6 alkoxy, C1-6 acyl, C1-6 alkylthio, or C1-6 alkoxycarbonyl;
R46 and R47 at each occurrence are the same or different and are
a) H,
b) phenyl,
c) C1-6 alkyl, or
d) benzyl;
R50 and R51 at each occurrence are the same or different and are
a) H,
b) OH,
c) C1-6 alkyl optionally substituted with xe2x80x94NR48R49 in which R48 and R49 are as defined above,
d) R50 and R51 taken together are xe2x95x90O;
R52 is
a) an aromatic moiety having 6 to 10 carbon atoms,
b) a 5- or 6-membered aromatic optionally benzo-fused heterocyclic moiety having one to three atoms selected from the group consisting of S, N, and O, wherein the substituents (a) and (b) can in turn be optionally substituted with one or three xe2x80x94NO2, CF3, halo, xe2x80x94CN, OH, phenyl, C1-5 alkyl, C1-5 alkoxy, or C1-5 acyl,
c) morpholinyl,
d) OH,
e) C1-6 alkoxy,
f) xe2x80x94NR48R49 in which R48 and R49 are as defined above,
g) xe2x80x94C(xe2x95x90O)xe2x80x94R59, or 
R53 is
a) H,
b) formyl,
c) C1-4 alkyl,
d) C1-4 acyl,
e) phenyl,
f) C3-6 cycloalkyl,
g) xe2x80x94P(O)(OR37)(OR38), or
h) xe2x80x94SO2R39, in which R37, R38 and R39 are as defined above;
R59 is
a) morpholinyl,
b) OH, or
c) C1-6 alkoxy;
h is 1, 2, or 3;
i is 0, 1, or 2;
j is 0, or 1;
k is 3, 4, or 5;
r is 1, 2, 3, 4, 5 or 6;
t is0, 1, 2, 3, 4, 5, or 6;
u is 1 or 2; and
Q is
a) hydrogen,
b) halo,
c) NO2,
d) N3,
e) C1-C6 alkylthio, 
h) C1-C6 alkyl,
i) C1-C6 alkoxy,
j) formyl, 
m) xe2x80x94sulfamoyl (H2NSO2-),
n) xe2x80x94NHOH, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 
r) amino,
s) C1-C6 alkylamino-,
t) di (C1-C6 alkyl)amino-, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
v) OH,
w) cyano,
x) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
xe2x80x83in which R84 is hydrogen or C1-6 alkyl, 
xe2x80x83in which R85 is hydrogen, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy; 
xe2x80x83in which R84 is hydrogen or C1-6 alkyl,
ff) a substituted or unsubstituted C6-C10 aryl moiety,
gg) a substituted or unsubstituted monocyclic or bicyclic, saturated or unsaturated, heterocyclic moiety having 1-3 atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent,
hh) a monocyclic or bicyclic substituted or unsubstituted heteroaromatic moiety having 1-3 hetero atoms selected from O, N or S, said ring being bonded via a ring carbon or nitrogen to the phenyl substituent and wherein the heteroaromatic moiety can additionally have a fused-on benzene or naphthalene ring;
the substituents for such p, q, ff, gg and hh moieties being selected from 1 or 2 of the following:
1) halo,
2) C1-6 alkyl,
3) NO2,
4) N3, 
7) formyl, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
13) OH,
14) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
18) xe2x80x94CH2xe2x80x94R80 in which R80 is
a) xe2x80x94OR32 in which R32 is as defined above,
b) xe2x80x94SR32 in which R32 is as defined above,
c) xe2x80x94NR32R33 in which R32 and R33 are as defined above,or
d) 5- or 6-membered heteroaromatic containing 1-4 O, S or N atoms, 
xe2x80x83in which R84 is as defined above,
20) cyano,
21) carboxyl,
22) CF3, 
xe2x80x83in which the phenyl moiety may be optionally substituted by halo or (C1-C6)alkyl, 
xe2x80x83in which R60 and R61 are as defined above, 
xe2x80x83in which R91 is a 5- or 6-membered aromatic heterocyclic group having 1-3 O, N or S,
27) 
28) 
xe2x80x83in which R85 is as defined above,
29) 
xe2x80x83in which R99R100 and R101 are each independently C1-6 alkyl; or
Q and either R1 and R2 taken together form xe2x80x94Oxe2x80x94CH2xe2x80x94O.
The compounds of this invention are novel and represent a new class of antibacterial agents. They are distinct from both the previously reported oxazolidinone and isoxazoline antibiotics since they incorporate the isoxazolinone ring system. They differ from the prior art isoxazolinone herbicides since the ring nitrogen must be substituted with an amide moiety as defined above.
The compounds of formula I are antibacterial agents useful in the treatment of infections in humans and other animals caused by a variety of bacteria, particularly methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. 
Also included in the invention are processes for preparing the compounds of formula I and pharmaceutical compositions containing said compounds in combination with pharmaceutically acceptable carriers or diluents.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein is intended to include the non-toxic acid addition salts with inorganic or organic acids, e.g. salts with acids such as hydrochloric, phosphoric, sulfuric, maleic, acetic, citric, succinic, benzoic, fumaric, mandelic, p-toluene-sulfonic, methanesulfonic, ascorbic, lactic, gluconic, trifluoroacetic, hydroiodic, hydrobromic, and the like. These salts may be in hydrated form.
The terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d includes chloro, bromo, fluoro and iodo, and is preferably chloro or fluoro.
The aliphatic xe2x80x9calkylxe2x80x9d groups as used herein means straight or branched chains having the specified number of carbon atoms, e.g. in the case of C1-C6 alkyl, the alkyl group may have from 1 to 6 carbon atoms.
Similarly, terms such as xe2x80x9cC2-C8 alkenylxe2x80x9d refer to at least one double bond alkenyl group having the specified number of carbon atoms, xe2x80x9cC2-C8 alkenylxe2x80x9d refers to at least one triple bond alkynyl group having the specified number of carbons, etc.
The term xe2x80x9cacyloxyxe2x80x9d unless otherwise defined refers to a group of the type 
where the alkyl group can have the specified number of carbon atoms, e.g. C1-C6 alkoxy would have 1-6 carbons. Where not specified the carbon length is from 1-6 carbons,
Unless otherwise indicated the term xe2x80x9carylxe2x80x9d refers to aromatic carbocyclic rings, i.e. phenyl and naphthyl.
xe2x80x9cHeteroaromaticxe2x80x9d as used herein refers to an aromatic heterocyclic moiety having one or more atoms selected from O, N, S, e.g. pyridine, thiophene, furan, pyrimidine, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 3-pyrazinyl, 2-quinolyn, 3-quinolyn, 1-isoquinolyl, 3-isoquinolyl, 2-imadazolyl, 4-imadazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-indolyl, 3-indolyl, 3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-furanyl, 3-furanyl, 2-thienyl, 3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,4-thiazol-3-yl, 1,2,4-thiazol-5-yl, 1,2,3,4-tetrazol-5-yl, 5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl, 1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl, 1-purinyl, 3-isothiazolyl, 4-isothiazolyl, and 5-isothiazolyl.
A saturated or unsaturated heterocyclic group can have 1-3 atoms selected from O, N and S, e.g. dioxolane, imidazolidine, dithiolane, oxathiolane, oxazolidine, piperidinyl, piperazinyl, morpholino or thiomorpholino, or the corresponding unsaturated heterocyclic groups.
Where possible nitrogen and/or sulfur atoms in such heterocyclic moieties may be oxidized and such oxidized compounds are intened to be encompassed within the formula I compounds.
Preferred embodiments of the present invention are the compounds of formula I wherein A is 
in which Q1, R2, and R3 are as defined above.
A still more preferred embodiment of the present invention comprises a compound of the formula 
or a pharmaceutically acceptable salt thereof, in which
R1 is H, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy, or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy;
R2 and R3 are each independently
a) H,
b) F,
c) Cl,
d) Br,
e) C1-6 alkyl,
f) NO2,
g) I,
h) C1-6 alkoxy,
i) OH
j) amino, or
k) cyano; and
Q is
a) hydrogen,
b) halo,
c) NO2,
d) N3,
e) C1-C6 alkylthio, 
h) C1-C6 alkyl,
i) C1-C6 alkoxy,
j) formyl, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S, 
p) amino,
q) C1-C6 alkylamino-,
r) di(C1-C6 alkyl)amino-, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
t) OH,
u) cyano,
v) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
xe2x80x83wherein R84 is hydrogen or C1-6 alkyl, 
xe2x80x83in which R85 is hydrogen, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy, 
xe2x80x83which R84 is as defined above, 
xe2x80x83in which R92 is H or C1-6 alkyl, 
aaa) a diazinyl group optionally substituted with X and Y,
bbb) a tiazinyl group optionally substituted with X and Y,
ccc) a quinolinyl group optionally substituted with X and Y,
ddd) a quinoxalinyl group optionally substituted with X and Y,
eee) a naphthyridinyl group optionally substituted with X and Y, 
B is an unsaturated 4-atom linker having one nitrogen and three carbons;
M is
a) H,
b) C1-8 alkyl,
c) C3-8 cycloalkyl,
d) xe2x80x94(CH2)mOR66, or
e) xe2x80x94(CH2)nNR67R68;
Z is
a) O,
b) S or
c) NM;
W is
a) CH,
b) N or
c) S or O when Z is NM;
X and Y are each independently
a) hydrogen,
b) halo,
c) NO2,
d) N3,
e) C1-6 alkythio, 
h) C1-C6 alkyl,
i) C1-C6 alkoxy,
j) formyl, 
xe2x80x83in which heteroaryl is a 5- or 6-membered aromatic heterocyclic group having 1-3 hetero atoms selected from O, N or S. 
o) amino,
p) C1-C6 alkylamino-,
q) di(C1-C6 alkyl)amino-, 
xe2x80x83in which R60 and R61 are each independently hydrogen or C1-C6 alkyl,
s) OH,
t) hydroxy (C1-C6 alkyl), 
xe2x80x83in which r is 1-6, 
xe2x80x83in which R84 is as defined above,
z) cyano,
aa) carboxyl,
bb) CF3,
cc) mercapto, 
xe2x80x83in which the phenyl moiety may be optionally substituted by halo or C1-C6 alkyl, 
xe2x80x83in which R85 is as defined above, or 
xe2x80x83in which R99, R100 and R101 are each independently C1-6 alkyl; or
Q and either R1 and R3 taken together form xe2x80x94Oxe2x80x94CH2xe2x80x94O;
R62 is
a) H,
b) C1-8 alkyl optionally substituted with one or more halos, or
c) C1-8 alkyl optionally substituted with one or more OH, or C1-8 alkoxy;
E is
a) NR69, 
b) xe2x80x94S(xe2x95x90O)i in which i is 0, 1 or 2, or
c) O;
R63 is
a) H,
b) C1-6alkyl,
c) xe2x80x94(CH2)q-aryl, or
d) halo;
R66 is H or C1-4 alkyl;
R67 and R68 are each independently H or C1-4 alkyl, or NR67R68 taken together are xe2x80x94(CH2)mxe2x80x94;
R69 is
a) H,
b) C1-6 alkyl,
c) xe2x80x94(CH2)qxe2x80x94aryl,
d) xe2x80x94CO2R81,
e) COR82,
f) xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)qxe2x80x94C(xe2x95x90O)R81,
g) xe2x80x94S(xe2x95x90O)zxe2x80x94C1-6 alkyl,
h) xe2x80x94S(xe2x95x90O)zxe2x80x94(CH2)qxe2x80x94aryl, or
i) xe2x80x94(Cxe2x95x90O)jxe2x80x94Het in which j is 0 or 1;
Z1 is
a) xe2x80x94CH2xe2x80x94, or
b) xe2x80x94CH(R70)xe2x80x94CH2xe2x80x94;
Z2 is
a) xe2x80x94O2Sxe2x80x94,
b) xe2x80x94Oxe2x80x94,
c) xe2x80x94Sxe2x80x94,
d) xe2x80x94SOxe2x80x94, or
e) xe2x80x94N(R71)xe2x80x94;
Z3 is
a) S,
b) SO,
c) SO2, or
d) O;
A1 is H or CH3;
A2 is
a) H,
b) OHxe2x80x94,
C) CH3CO2xe2x80x94,
d) CH3xe2x80x94,
e) CH3Oxe2x80x94,
f) R72Oxe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94,
g) R73O xe2x80x94C(O)xe2x80x94NHxe2x80x94,
h) R73xe2x80x94C(O)xe2x80x94NHxe2x80x94,
i) (C1-C2)alkyl-Oxe2x80x94C(O)xe2x80x94, or
j) HOxe2x80x94CH2; or
A1 and A2 taken together are 
b) Oxe2x95x90;
R64 is H or CH3xe2x80x94;
m is 4 or 5;
n is 0, 1, 2, 3, 4 or 5;
y is 0 or 1;
p is 0, 1, 2, 3, 4 or 5;
w is 1, 2 or 3;
q is 1, 2, 3 or 4;
z is 0 or 1;
R65 is
a) R74OC(R75)(R76)xe2x80x94C(O)xe2x80x94,
b) R77OC(O)xe2x80x94,
c) R78(O)xe2x80x94,
d) R79xe2x80x94SO2xe2x80x94, or
e) R80xe2x80x94NHxe2x80x94C(O)xe2x80x94;
R70 is H or (C1-C3)alkyl;
R71 is
a) R74OC(R75)(R76)xe2x80x94C(O)xe2x80x94,
b) R77Oxe2x80x94C(O)xe2x80x94,
c) R78xe2x80x94C(O)xe2x80x94, 
f) H3C-C(O)-(CH2)2xe2x80x94C(O)xe2x80x94,
g) R79xe2x80x94SO2xe2x80x94, 
i) R80xe2x80x94NHxe2x80x94C(O)xe2x80x94,
R72 is
a) H.
b) CH3,
c) phenyl xe2x80x94CH2xe2x80x94, or
d) CH3C(O)xe2x80x94;
R73 is (C1-C3)alkyl or phenyl;
R74 is H, CH3, phenyl-CH2xe2x80x94 or CH3xe2x80x94C(O)xe2x80x94;
R75 and R76 are each independently H or CH3, or R75 and R76 taken together are xe2x80x94CH2CH2xe2x80x94;
R77 is (C1-C3)alkyl or phenyl;
R78 is H, (C1-C4)alkyl, aryl-(CH2)n1, ClH2C, Cl2HC, FH2Cxe2x80x94, F2HCxe2x80x94 or (C3-C6)cycloalkyl;
R79 is CH3; xe2x80x94CH2Cl, xe2x80x94CH2CHxe2x95x90CH2, aryl or xe2x80x94CH2CN;
R80 is CH2)n1-aryl where n1 is 0 or 1;
R81 is
a) H,
b) C1-6 alkyl optionally substituted with one or more OH, halo or CN,
c) xe2x80x94(CH2)q-aryl in which q is as defined above, or
d) xe2x80x94(CH2)qxe2x80x94OR83 in which q is as defined above;
R82 is
a) C1-6 alkyl optionally substituted with one or more OH, halo or CN,
b) xe2x80x94(CH2)q-aryl in which q is as defined above, or
c) xe2x80x94(CH2)qxe2x80x94OR83 in which q is as defined above;
R83 is
a) H,
b) C1-6 alkyl,
c) xe2x80x94(CH2)q-aryl in which q is as defined above; or
d) xe2x80x94C(xe2x95x90O) C1-6 alkyl; and
aryl is phenyl, pyridyl or naphthyl, said phenyl, pyridyl or naphthyl moieties being optionally substituted by one or more halo, xe2x80x94CN, OH, SH, C1-6 alkoxy or C1-6 alkylthio.
Another preferred embodiment of the present invention comprises a compound of the formula 
or a pharmaceutically acceptable salt thereof, in which
R1 is H, C1-8 alkyl optionally substituted with one or more F, Cl, OH, C1-8 alkoxy or C1-8 acyloxy, C3-6 cycloalkyl or C1-8 alkoxy;
R2 and R3 are each independently H or F; or R2 and R3 taken together represent 
a) hydrogen,
b) halo,
c) N3,
d) NO2,
e) C1-C6 alkylthio, 
h) C1-C6 alkyl,
i) C1-C6 alkoxy,
j) formyl, 
n) (C1xe2x80x94C6 alkoxy)2Nxe2x80x94,
o) 5- or 6-membered heterocyclic containing 1-3 O, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by R96, 
q) phenyl optionally substituted by R96, or
r) 5- or 6-membered saturated or unsaturated heterocyclic containing 1-3 O, N or S and linked to the phenyl substituent via a carbon or nitrogen, said heterocycle moiety being optionally substituted by R96, and
R96 is
a) C1-C6 alkyl-OH, 
d) cyano,
e) formyl, 
xe2x80x83in which R99, R100 and R101, are each independently C1-6 alkyl, 
xe2x80x83where the phenyl may be optionally substituted by halo, 
m) (C1-C6 alkyl)2Nxe2x80x94,
n) C1-C6 alkyl-NHxe2x80x94,
o) amino, 
xe2x80x83in which R98 is phenyl, 5- or 6-membered heteroaryl containing 1-3 O, N or S and linked to the phenyl substituent via a ring carbon atom or 5- or 6-membered saturated or unsaturated heterocyclic containing 1-4 O, N or S and linked to the phenyl substituent via a ring carbon atom.
Some specific preferred embodiments of the present invention are listed in the table below. 
The compounds of the present invention can be made by the methods summarized below.
It will be apparent to those skilled in the art that the procedures described herein are representative in nature and that alternative procedures are feasible.
Isoxazolinones 5 of the present invention are preferably prepared via the sequence outlined in Scheme 1. Aryl acetic acids 1 are either commercially available or prepared by one of many well known methods in the chemical literature including but not limited to the sequence shown in Scheme 2 or 3. Isoxazolinone 3 is prepared by methods described by Marchesini [J. Org. Chem. 1984, 49, p. 4287-4290]. Reaction of 1 with sodium hydride and ethyl formate provides 2 which is in turn reacted with hydroxylamine yielding 3. Treatment of 3 with mild base, preferably potassium carbonate, in an appropriate solvent, preferably dichloromethane or N,N-dimethylformamide followed by addition of 4 (prepared by methods described by Barnes et al in U.S. Pat. No. 5,284,863) provides isoxazolinone 5. 
An alternative way to prepare aryl acetic esters 1 of the present invention is shown in Scheme 2. Treatment of triflate 6 (prepared from methyl 4-hydroxyphenyl acetate by methods known by those skilled in the art) with an N,N-dialkylamine in the manner described by Buchwald [Tet. Lett., 1997, 38, p. 6363-6366] produces esters exemplified by 7. Aryl-bromides, -iodides, and -chlorides are also suitable as replacements for triflate 6 in Scheme 2. The N,N-dialkylamines used in Scheme 2 are either commercially available or are synthesized by literature procedures. Literature preparations of many cyclic N,N-dialkylamines have been detailed by Gadwood (WO 97/10223) and others are well known to those skilled in the art. 
Another alternative to prepare aryl acetic esters 1 of the present invention is shown in Scheme 3. Treatment of 8 with a mild base, preferably potassium carbonate, and a primary or secondary amine or thiolate, in a suitable solvent, preferably acetonitrile or N,N-dimethylformamide, at a temperature between 25xc2x0 C. and 100xc2x0 C. provides 9. Compound 8 is commercially available. Compound 9 is converted to 11 or 12 by methods described by Gravestock (World Patent 97/14690). This sequence is also known to those skilled in the art as the Wiligerodt reaction. Conversion of 11 to 12 can also be accomplished by various methods known in the chemical literature including but not limited to treatment with acid in hot alcohol. 
Sulfoxides and sulfones 14 and 16 are prepared by treating sulfides 13 and 15, respectively with an oxidizing agent such as m-chloroperoxybenzoic acid or osmium tetroxide by methods known by those skilled in the art and exemplified by Barbachyn [J. Med. Chem., 1996, 39, 680-685]. 
An alternative method of preparing compound 18 of the present invention is shown in Scheme 5. Treatment of 17 with an appropriate organostannane provides 18. This method is known by those skilled in the art as the Stille cross-coupling reaction. 
Preparation of 21, 22, 23, and 24 of the present invention is described in Scheme 6. Treatment of 19 with trifluoroacetic acid provides 20. Compound 20 is treated with an acid chloride, chloroformate, sulfonyl halide, or isocyanate in the presence of triethylamine by methods well known in the chemical literature to provide 21, 22, 23, and 24, respectively. 
The triazole-substituted compounds 27 and 28 are prepared by cyclization of the azide 25 with acetylenes 26 (Scheme 7). This is a standard 3+2 cycloaddition which is well documented in the chemical literature. The acetylenes 26 are either commercially available or prepared by literature procedures. For example, cyanoacetylene is prepared according to Murahashi [J.Chem. Soc. Jap., 1956, 77, 1689]. The cyclization reaction was usually carried out in a suitable solvent such as DMF, at a temperature between 25xc2x0 C. and 80xc2x0 C. Other suitable solvents include but are not limited to DMSO, NMP, and DMA. The two cyclization adducts 27 and 28 were separated using preparative HPLC or by triturating with a suitable solvent such as ethyl acetate. Other suitable solvents for trituration include but are not limited to methanol, ethanol, diethyl ether, and acetone. 
The azidophenylisoxazolinone 25 is reduced to aminophenylisoxazolinone 29 via one of the many well known methods in the chemical literature including but not limited to the treatment with stannous chloride in a suitable solvent such as a 2:1 combination of ethyl acetate and methanol. Treatment of aminophenylisoxazolinones 29 with 2,5-dimethoxytetrahydrofurans 30 in acetic acid provide pyrrole-substituted isoxazolinones 31 (Scheme 8). Subsequent conversions of the pyrrole (R=CHO) are also possible, for instance the corresponding oxime can be prepared by refluxing with 50% aqueous hydroxylamine in methanol. 
N-thioacetates 33 may be prepared from the corresponding N-acetates 32 using a variety of well known literature methods, for instance by refluxing in benzene with Lawesson""s reagent. Other solvents such as toluene and xylene are also suitable. 
It will be understood that where the substituent groups used in the above reactions contain certain reaction-sensitive functional groups which might result in undesirable side-reactions, such groups may be protected by conventional protecting groups known to those skilled in the art. Suitable protecting groups and methods for their removal are illustrated, for example, in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley and Sons, 1991). It is intended that such xe2x80x9cprotectedxe2x80x9d intermediates and end-products are included within the scope of the present disclosure and claims.
Some of the desired end-products of formula I contain an amine. In these cases, the final product may be recovered in the form of a pharmaceutically acceptable acid addition salt, e.g. by addition of the appropriate acid such as HCl, HI or methane-sulfonic acid to the amine.
It will be appreciated that certain products within the scope of formula I may have substituent groups which can result in formation of optical isomers. It is intended that the present invention include within its scope all such optical isomers as well as epimeric mixtures thereof, i.e. R- or S- or racemic forms.
The compounds of the invention are useful because they possess pharmacological activities in animals, including particularly mammals and most particularly, humans. The novel isoxazolinone derivatives of general formula I , or pharmaceutically acceptable salts or prodrugs thereof, are potent antibiotics active against gram-positive bacteria. While they may be used, for example, as animal feed additives for promotion of growth, as preservatives for food, as bactericides in industrial applications, for example in waterbased paint and in the white water of paper mills to inhibit the growth of harmful bacteria, and as disinfectants for destroying or inhibiting the growth of harmful bacteria on medical and dental equipment, they are especially useful in the treatment of bacterial infections in humans and other animals caused by the gram-positive bacteria sensitive to the new derivatives.
The pharmaceutically active compounds of this invention may be used alone or formulated as pharmaceutical compositions comprising, in addition to the active isoxazolinone ingredient, a pharmaceutically acceptable carrier or diluent. The compounds may be administered by a variety of means, for example, orally, topically or parenterally (intravenous or intramuscular injection). The pharmaceutical compositions may be in solid form such as capsules, tablets, powders, etc. or in liquid form such as solutions, suspensions or emulsions. Compositions for injection may be prepared in unit dose form in ampules or in multidose containers and may contain additives such as suspending, stabilizing and dispersing agents. The compositions may be in ready-to-use form or in powder form for reconstitution at the time of delivery with a suitable vehicle such as sterile water.
Thus, according to another aspect of the invention, there is provided a method of treating a bacterial infection which comprises administering a therapeutically effective amount of the compound to a host, particularly a mammalian host and most particularly a human patient. The use of the compounds of the present invention as pharmaceuticals and the use of the compounds of the invention in the manufacture of a medicament for the treatment of bacterial infections are also provided.
The dosage to be administered depends, to a large extent, on the particular compound being used, the particular composition formulated, the route of administration, the nature and condition of the host and the particular situs and organism being treated. Selection of the particular preferred dosage and route of application, then, is left to the discretion of the physician or veterinarian. In general, however, the compounds may be administered parenterally or orally to mammalian hosts in an amount of from about 25 mg/day to about 2 g/day.
The preparations of pyrazoles substituted compounds are outlined in Scheme 10. Compound 29 was diazotized and then reduced to form hydrazine hydrochloride salt 34 via one of the many well known methods in the chemical literature including but not limited to the treatment with sodium nitrite and stannous chloride. Treatment of 34 with ethoxycarbonylmalondiadehyde, cyanomalondiadehyde [prepared according to Bertz, S. H., Dabbagh, G. and Cotte, P. in J. Org. Chem, 1982, 47, p. 2216,] or malondiadehyde [prepared according to Martinez, A. M., Cushmac, G. E., Rocek, J. in J. Amer. Chem. Soc, 1975, 97, p. 6502] in the presence of sodium bicarbonate at room temperature provides compound 35. 
In Vitro Activity
Samples of the compounds prepared below in Examples 1-97 after solution in water and dilution with Nutrient Broth were found to exhibit the following ranges of Minimum Inhibitory Concentrations (MIC) versus the indicated microorganisms as determined by tube dilution. The MICs were determined using a broth micro dilution assay in accordance with that recommended by the National Committee for Clinical Laboratory Standards (NCCLS). Mueller-Hinton medium was used except for Streptococci which was tested in Todd Hewitt broth. The final bacterial inoculate contained approximately 5xc3x97105 cfu/ml and the plates were incubated at 35xc2x0 C. for 18 hours in ambient air (Streptococci in 5% CO2). The MIC was defined as the lowest drug concentration that prevented visible growth.